Our interest has centered around factors which regulate ketone-body (acetoacetate and beta-hydroxybutyrate) metabolism in the human. Specifically, we have focused our attention on (i) the production and removal rates of ketone bodies; (ii) the distribution of these compounds in various water compartments of the body; (iii) the excretion of ketone bodies by the kidney; and (iv) hormones that modify ketone body metabolism. First we have reported that ketone bodies are largely limited to the extracellular spaces in humans and animals. Therefore, small increases in hepatic ketone-body production result in disproportionate increases in the bloodstream concentrations. Second, the linear relationship between ketone-body utilization rates and ketone-body concentration dissolves when the total circulating concentration exceeds 2-3 mmol/liter. Furthermore, the rate of peripheral tissue removal rather than the rate of hepatic production is primarily responsible for determining circulating concentrations of ketone bodies during starvation ketoacidosis. Third, renal reabsorption of ketone bodies increases during starvation, thus minimizing not only ketone-body losses in the urine but also urinary ammonium losses derived from proteolysis. Such a retrieval of ketone bodies by the kidneys not only conserves valuable body nitrogen and fuels but also aids in maintaining high circulating concentrations of acetoacetate and beta- hydroxybutyrate which can successfully compete with glucose for central nervous system metabolism.